Abstract

The use of 5‐aminolevulinic acid (ALA) administration has led to many applications of photodynamic therapy
(PDT) in cancer. However, the hydrophilic nature of ALA limits its ability to penetrate the cells and tissues, and therefore the need for ALA derivatives became an urgent research target. In this study we investigated the activity of novel multifunctional acyloxyalkyl ester prodrugs of ALA that upon metabolic hydrolysis release active components such as, formaldehyde, and the histone deacetylase inhibitory moiety, butyric acid. Evaluation of these prodrugs under photo‐irradiation conditions showed that butyryloxyethyl 5‐amino‐4‐oxopentanoate (ALA‐BAC) generated the most efficient photodynamic destruction compared to ALA. ALA‐BAC stimulated a rapid biosynthesis of protoporphyrin IX (PpIX) in human glioblastoma U‐251 cells which resulted in generation of intracellular ROS, reduction of mitochondrial activity, leading to apoptotic and necrotic death of the cells. The apoptotic cell death induced by ALA / ALA‐BAC followed by PDT equally activate intrinsic and extrinsic apoptotic signals and both pathways may occur simultaneously. The main advantage of ALA‐BAC over ALA stems from its ability to induce photo‐damage at a significantly lower dose than ALA.